Introduction

Barth syndrome (BTHS) is a rare X-linked disorder characterized by multiple associated abnormalities, including cyclic neutropenia, skeletal myopathy, cardiomyopathy, mitochondrial functional impairment, 3-methylglutaconic aciduria, lactic acidosis, growth deficiency, and cardiolipin deficiency [3]. The genetic basis of BTHS has been identified as the taffazin (TAZ) gene, previously called “G4.5” [3, 7]. Diagnosis of BTHS is often made during infancy when the patient is diagnosed with new-onset cardiomyopathy. A number of early studies on the infantile and pediatric forms of BTHS have demonstrated early-onset cardiomyopathy with diagnosis at several weeks to an average diagnosis at 5.5 months of age [12]. Clinical severity and type of cardiomyopathy is variable, but most BTHS individuals have been diagnosed with dilated cardiomyopathy, and it has been shown that many have a pattern of deep myocardial trabeculations and intertrabecular recesses consistent with a diagnosis of left-ventricular noncompaction (LVNC) cardiomyopathy [9, 11]. Studies have suggested that many BTHS patients with cardiomyopathy are responsive to medical management; however, severe heart failure unresponsive to standard medical management resulting in uncontrolled decompensated heart failure requiring heart transplant has been described [1, 8]. Adwani et al. [1] reported a case of the first successful heart transplant in 1997 in BTHS. Since that report, heart transplantation has become recognized as an effective method for the management of end-stage heart failure in BTHS as it is for other forms of pediatric and adult heart failure.

Unfortunately, there continues to be significant morbidity and mortality in children awaiting heart transplantation. Currently pediatric heart transplantation has the highest waiting-list mortality compared with all other age groups and all other solid organ transplants [2]. Therefore, the use of ventricular assist devices (VADs) has grown in popularity during the past decade with encouraging results [4, 10]. Here we report the first documented case of the use of a VAD as a bridge to cardiac transplantation in a patient with BTHS. This is also the first report on the postoperative use of a membrane oxygenator, in line with a right-sided assist device, as a means to allow recovery of pulmonary function.

Case Report

A male infant presented at day 3 of life in cardiogenic shock with multiorgan failure. His initial echocardiogram showed left-ventricular hypertrophy and severe biventricular dysfunction with an initial ejection fraction (EF) 25% (normal 50–65%), fractional shortening (FS) 15% (normal 35–45%), and normal left-ventricular diastolic dimension 1.8 cm. The left atrium was enlarged, and there was mild mitral regurgitation and deep myocardial trabeculations consistent with LVNC. In the neonatal intensive care unit, an attempt to support his cardiac output with routine inotropic agents was made without success. He was transferred to the cardiac intensive care unit (CICU) to be evaluated for mechanical circulatory support due to persistent end-organ dysfunction. A calcium chloride infusion was initiated with subsequent improvement of his cardiac output. Routine genetic evaluation, high-resolution chromosomes, and a single-nucleotide polymorphism microarray were performed and were normal. The LVNC evident on echocardiogram, along with a family history of a maternal uncle who had died from heart failure in infancy, prompted further genetic testing and metabolic analysis. Genetic screening revealed a deletion of exons 1 through 5 of the TAZ gene, consistent with BTHS.

After the initial resuscitation, the patient required prolonged hospitalization as he was weaned from intravenous inotropes and transitioned to oral medications (diuretics and angiotensin-converting inhibitors [ACEI]). His end-organ function waxed with changes in his cardiac and immune function (Table 1). His BTHS-associated immune dysfunction led to many nosocomial infections despite supplementation with granulocyte colony-stimulating factor (GCSF).

Table 1 Clinical data (laboratory values) before transplant
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His echocardiogram at initial presentation at day 3 days of life demonstrated a hypertrophic form of left-ventricular noncompaction (posterior wall z score 3.4) with poor systolic function. At 12 months of age he had severe myocardial dysfunction with left-ventricular dilation (Fig. 1) and regression of myocardial wall hypertrophy (posterior wall z score −1.27), consistent with the concept of “undulating phenotype” reported in patients with LVNC [11]. Interestingly, he did have a several-month period of stability before further deteriorating (Table 2).

Fig. 1
figure 1

Echocardiogram of cardiac morphology at time of cardiac decompensation. There is evidence of left-ventricular noncompaction (arrow). There are deep recesses with prominent trabeculations

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Table 2 Echocardiographic data before transplant
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When the patient’s cardiac function reached a nadir, EF < 15%, he had increased symptoms of congestive heart failure requiring readmission to the CICU. He quickly required inotropic support with minimal improvement; simultaneously he was evaluated and listed for transplantation. Special consideration was given to his underlying genetic diagnosis and comorbidities before he was listed. Since most BTHS-associated mortality is due to cardiac failure, cardiac replacement should allow for a life expectancy that is now only limited by the viability of the donor organ [3]. The decision regarding further medical management versus mechanical circulatory support was debated due to his history of multiple nosocomial infections, commonly a result of indwelling catheters. Nonetheless, despite maximal medical support, he developed worsening cardiac failure and developed refractory ventricular tachycardia prompting the urgent placement of an EXCOR (Berlin Heart, Berlin Germany) biventricular assist device (Bi-VAD).

In the operating room, cannulas were inserted in the left ventricle and aorta, and a 10-ml EXCOR left-ventricular assist device (LVAD) was placed. Despite his return to normal sinus rhythm, after unloading of the left ventricle, the patient continued to have borderline hemodynamics after separation from cardiopulmonary bypass (CPB). Intraoperative transesophageal echocardiogram demonstrated severely depressed right-ventricular function with dilation and ventricular septal bowing, which led to compromised filling of the left-sided inflow cannula. Therefore, a 10-ml EXCOR right-ventricular assist device (RVAD) was placed with cannulation of the right atrium and pulmonary artery. The second separation from CPB was complicated by pulmonary hemorrhage leading to poor oxygenation and ventilation. The high airway pressures required to oxygenate the patient led to an increase in pulmonary vascular resistance, poor RVAD ejection, and dismal LVAD filling. A Quadrox-iD Pediatric membrane oxygenator (Maquet, Inc. Wayne, NJ, USA) was placed in-line with outflow cannula of the RVAD. The RVAD outflow cannula was connected to a 0.25-in. tube that was inserted into the inflow of the membrane oxygenator. A second 0.25-in. tube was connected from the membrane oxygenator to the pulmonary artery cannula (Fig. 2a, b). The addition of the membrane oxygenator resulted in immediate improvement in hemodynamics. He was taken back to the CICU with an open chest.

Fig. 2
figure 2

a The Bi-VAD circuit with the addition of standard 0.25-in. ECMO tubing connecting the RVAD to the oxygenator. The asterisk signifies the tubing that returns from the oxygenator with fully oxygenated blood to the pulmonary artery. The arrows show the direction of blood flow. b In the photograph of the entire system, the oxygenator is positioned above the patient. The arrows follow the blood flow

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After surgery, the patient’s lung recovery was achieved with the use of biphasic ventilator (Bi-Vent) strategy and surfactant administration with rapid improvement in lung compliance. The membrane oxygenator was removed on postoperative day 6; however, he developed significant bleeding and tamponade the next day, which prompted mediastinal re-exploration and subsequent membrane oxygenator replacement due to transfusion induced lung injury. Coagulation was altered significantly when the additional tubing and oxygenator was removed, leading to excessive heparinization, and ultimately required surgical intervention. Anticoagulation according to the Berlin Heart protocol could not be achieved, and he developed numerous fibrin thrombi in the LVAD and the oxygenator, prompting replacement of both mechanical devices 9 days after initial Bi-VAD placement. Bleeding was eventually controlled and the second oxygenator was removed 11 days after placement. Despite the postoperative bleeding, he remained hemodynamically stable with adequate end-organ perfusion. Although his BTHS-associated neutropenia was evident and necessitated surveillance cultures and GCSF throughout his hospitalization, he did not have severe infectious complications. He underwent successful cardiac transplantation 24 days after initial Bi-VAD placement and discharged home 6 weeks after transplantation.

Discussion

Cardiac disease in BTHS usually presents in infancy and stabilizes with anti-heart failure medications (diuretics, ACEI, β-blockers). With today’s improved pharmacological regimen and close surveillance, sudden cardiac failure is uncommon. However, the cardiomyopathy phenotype of children with BTHS can “undulate,” thus requiring a change in medical therapy (i.e., degree of dysfunction and change from hypertrophic to dilated phenotype) and, if unresponsive to medication changes, may necessitate transplantation [11].

Children with BTHS are thought to be high-risk transplant candidates because of their associated immunocompromised system, generalized myopathy, and suspected coagulopathy, but there have been reports of successful transplantation in this subset of patients [1]. The comorbidities that occur with BTHS, in particular their insufficient immune system (neutropenia), increases the risk of nosocomial infections, thus leading to sepsis and death while awaiting transplantation. In the general pediatric population, mechanical support devices (extracorporeal membrane oxygenator [ECMO] and VADs) have been increasingly used in children with heart failure as a bridge to transplantation [4, 10]. One of the most devastating complications of mechanical circulatory support is major infection and sepsis, occurring in 63% and 44% of patients on the Berlin device, respectively. At times these complications deem the patient unsuitable for transplantation or results in patient demise [13]. The infection risk in immunocompetent patients on mechanical support is so great that most centers have avoided using mechanical support in immunocompromised children. The limited experience published on the use of mechanical support in immunocompromised children has shown that only one in three immunocompromised children on ECMO for respiratory failure survive to hospital discharge [6]. To date, there has not been a published report of an immunocompromised pediatric patient being successfully supported on a VAD. This patient’s fragile immune state discouraged us from converting to conventional ECMO when he developed respiratory failure and incited the development of a novel mechanical support system. The use of a membrane oxygenator in line with the RVAD, to avoid a transition to conventional ECMO, makes this case even more unique.

In most instances, a patient with a rapid decrease in cardiac output would be placed on ECMO to quickly stabilize end-organ perfusion. ECMO would then act as a bridge, allowing time to obtain the EXCOR, to a longer-term support device. In this case, the EXCOR had been delivered and had been scheduled to be placed in a nonurgent fashion. Our patient presented a unique situation because he had a rapid decline in cardiac output, and we had the devices available. The patient was taken to the operating room; the Bi-VAD EXCOR devices were placed; and after being weaned from CPB the patient unexpectedly had severe respiratory failure. This unforeseen respiratory event was multifactorial due to the need for massive blood product transfusions and to the presence of high left atrial pressures before decompression of the left ventricle. With the cannulas in place, it was not feasible or optimal to convert the patient from the Berlin Heart to conventional ECMO.

As reported previously, a Quadrox oxygenator was incorporated into a VAD circuit [5]. Unlike the previously published case report, the Quadrox oxygenator was placed in series with the RVAD rather than the LVAD. The advantages to this configuration are three-fold. First, the addition of the oxygenator places the patient at increased risk for an air-emboli or thromboembolic event. The oxygenator being positioned in line with the RVAD allows the lungs to be a filter of air-emboli and thrombi. The second benefit is the lungs will be supplied with fully oxygenated arterial blood; theoretically this may improve lung recovery. This is a similar concept to venous–venous ECMO for severe respiratory failure. Finally, the afterload on the left is significantly higher than on the right; therefore, much higher pneumatic driving pressures are required. With the oxygenator in-line with the RVAD, we were required to use 65% higher drive pressures than normal. On the left, this kind of requirement would potentially exceed the performance capabilities of the system.

As the use of ventricular assist devices becomes more ubiquitous in pediatrics, challenges are likely to arise in treating unique patient populations, such as children with comorbid conditions, including immune dysfunction. This case represents the first reported experience with mechanical circulatory support in a patient with BTHS. Additionally, a novel circuit configuration allowed for a membrane oxygenator to be placed in series with the RVAD to allow favorable ventilator settings and lung recovery. Fortunately, these innovative technologies successfully bridged the child to cardiac transplantation and ultimately discharge to home.